1. Technical Field
The disclosure relates to pyrimidine and quinazoline derivatives and their use as anticancer drugs.
2. Description of Related Art
Overexpression of cancerous inhibitor of protein phosphatase 2A (abbreviated as CIP2A) has been found in several common human cancers including acute leukemia, prostate cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, colon cancer and breast cancer and has been linked to clinical aggressiveness in tumors and promotion of the malignant growth of cancer cells. CIP2A interacts directly with the transcription factor c-Myc and inhibits the PP2A dephosphorylation of c-Myc, thereby stabilizing the oncogenic c-Myc from degradation.
Protein phosphatase 2A (abbreviated as PP2A) is a crucial regulator of cell proliferation by dephosphorylation of protein kinases on serine or threonine residues. PP2A is composed of three subunits which regulate substrate specificity, cellular localization and enzymatic activity. For example, PP2A dephosphorylates p-Akt at serine 473 and reduces the cell growth. Hence, the CIP2A-PP2A-Akt signaling cascade is thought to be an important survival regulator in cancers. Accordingly, downregulation of c-Myc and p-Akt by CIP2A ablation is a promising anticancer strategy.
Some compounds have been found to be capable of repressing repress CIP2A expression and subsequently reducing p-Akt level and induce apoptosis in hepatocellular carcinoma (HCC). For example, the above phenomenon had been observed for bortezomib, a proteasome inhibitor.